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Toxicologic Evaluation for Amorphous Silica Nanoparticles: Genotoxic and Non-Genotoxic Tumor-Promoting Potential.

ABSTRACT: Amorphous silica nanoparticles (SiO2NPs) have been widely used in medicine including targeted drug/DNA delivery, cancer therapy, and enzyme immobilization. Nevertheless, SiO2NPs should be used with caution due to safety concerns associated with unique physical and chemical characteristics. The objective of this study was to determine the effects of SiO2NPs on genotoxic and non-genotoxic mechanisms associated with abnormal gap junctional intercellular communication (GJIC) in multistage carcinogenesis. The SiO2NPs exhibited negative responses in standard genotoxicity tests including the Ames test, chromosome aberration assay, and micronucleus assay. In contrast, the SiO2NPs significantly induced DNA breakage in comet assay. Meanwhile, SiO2NPs inhibited GJIC based on the results of scrape/loading dye transfer assay for the identification of non-genotoxic tumor-promoting potential. The reduction in expression and plasma membrane localization of Cx43 was detected following SiO2NP treatment. Particularly, SiO2NP treatment increased Cx43 phosphorylation state, which was significantly attenuated by inhibitors of extracellular signal-regulated kinases 1/2 (ERK1/2) and threonine and tyrosine kinase (MEK), but not by protein kinase C (PKC) inhibitor. Taken together, in addition to a significant increase in DNA breakage, SiO2NP treatment resulted in GJIC dysregulation involved in Cx43 phosphorylation through the activation of mitogen-activated protein kinase (MAPK) signaling. Overall findings of the genotoxic and non-genotoxic carcinogenic potential of SiO2NPs provide useful toxicological information for clinical application at an appropriate dose.

SUBMITTER: Lee GH

PROVIDER: S-EPMC7559769 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Toxicologic Evaluation for Amorphous Silica Nanoparticles: Genotoxic and Non-Genotoxic Tumor-Promoting Potential.

Lee Gwang-Hoon GH Kim Yun-Soon YS Kwon Euna E Yun Jun-Won JW Kang Byeong-Cheol BC

Pharmaceutics 20200829 9

Amorphous silica nanoparticles (SiO2NPs) have been widely used in medicine including targeted drug/DNA delivery, cancer therapy, and enzyme immobilization. Nevertheless, SiO2NPs should be used with caution due to safety concerns associated with unique physical and chemical characteristics. The objective of this study was to determine the effects of SiO2NPs on genotoxic and non-genotoxic mechanisms associated with abnormal gap junctional intercellular communicatio ...[more]

PMID: 32872498

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Project description:BackgroundThe regulatory definition(s) of nanomaterials (NMs) frequently uses the term 'agglomerates and aggregates' (AA) despite the paucity of evidence that AA are significantly relevant from a nanotoxicological perspective. This knowledge gap greatly affects the safety assessment and regulation of NMs, such as synthetic amorphous silica (SAS). SAS is used in a large panel of industrial applications. They are primarily produced as nano-sized particles (1-100?nm in diameter) and considered safe as they form large aggregates (>?100?nm) during the production process. So far, it is indeed believed that large aggregates represent a weaker hazard compared to their nano counterpart. Thus, we assessed the impact of SAS aggregation on in vitro cytotoxicity/biological activity to address the toxicological relevance of aggregates of different sizes.ResultsWe used a precipitated SAS dispersed by different methods, generating 4 ad-hoc suspensions with different aggregate size distributions. Their effect on cell metabolic activity, cell viability, epithelial barrier integrity, total glutathione content and, IL-8 and IL-6 secretion were investigated after 24?h exposure in human bronchial epithelial (HBE), colon epithelial (Caco2) and monocytic cells (THP-1). We observed that the de-aggregated suspension (DE-AGGR), predominantly composed of nano-sized aggregates, induced stronger effects in all the cell lines than the aggregated suspension (AGGR). We then compared DE-AGGR with 2 suspensions fractionated from AGGR: the precipitated fraction (PREC) and the supernatant fraction (SuperN). Very large aggregates in PREC were found to be the least cytotoxic/biologically active compared to other suspensions. SuperN, which contains aggregates larger in size (>?100?nm) than in DE-AGGR but smaller than PREC, exhibited similar activity as DE-AGGR.ConclusionOverall, aggregation resulted in reduced toxicological activity of SAS. However, when comparing aggregates of different sizes, it appeared that aggregates >?100?nm were not necessarily less cytotoxic than their nano-sized counterparts. This study suggests that aggregates of SAS are toxicologically relevant for the definition of NMs.

Project description:BackgroundInhalation of crystalline silica is known to cause an inflammatory reaction and chronic exposure leads to lung fibrosis and can progress into the disease, silicosis. Cultured macrophages bind crystalline silica particles, phagocytose them, and rapidly undergo apoptotic and necrotic death. The mechanism by which particles are bound and internalized and the reason particles are toxic is unclear. Amorphous silica has been considered to be a less toxic form, but this view is controversial. We compared the uptake and toxicity of amorphous silica to crystalline silica.Methodology/principal findingsAmorphous silica particles are phagocytosed by macrophage cells and a single internalized particle is capable of killing a cell. Fluorescent dextran is released from endo-lysosomes within two hours after silica treatment and Caspase-3 activation occurs within 4 hours. Interestingly, toxicity is specific to macrophage cell lines. Other cell types are resistant to silica particle toxicity even though they internalize the particles. The large and uniform size of the spherical, amorphous silica particles allowed us to monitor them during the uptake process. In mCherry-actin transfected macrophages, actin rings began to form 1-3 minutes after silica binding and the actin coat disassembled rapidly following particle internalization. Pre-loading cells with fluorescent dextran allowed us to visualize the fusion of phagosomes with endosomes during internalization. These markers provided two new ways to visualize and quantify particle internalization. At 37 °C the rate of amorphous silica internalization was very rapid regardless of particle coating. However, at room temperature, opsonized silica is internalized much faster than non-opsonized silica.Conclusions/significanceOur results indicate that amorphous and crystalline silica are both phagocytosed and both toxic to mouse alveolar macrophage (MH-S) cells. The pathway leading to apoptosis appears to be similar in both cases. However, the result suggests a mechanistic difference between Fc?RIIA receptor-mediated and non-opsonized silica particle phagocytosis.

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Toxicologic Evaluation for Amorphous Silica Nanoparticles: Genotoxic and Non-Genotoxic Tumor-Promoting Potential.

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Toxicologic Evaluation for Amorphous Silica Nanoparticles: Genotoxic and Non-Genotoxic Tumor-Promoting Potential.

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